DE69512930T2 - STILB DERIVATIVES USED AS CYCLOOXYGENASE-2 INHIBITORS - Google Patents

Abstract

PCT No. PCT/CA95/00601 Sec. 371 Date Apr. 7, 1997 Sec. 102(e) Date Apr. 7, 1997 PCT Filed Oct. 24, 1995 PCT Pub. No. WO96/13483 PCT Pub. Date May 9, 1996The invention encompasses novel compounds of Formula Iuseful in the treatment of cyclooxygenase-2 mediated diseases. <IMAGE> I The invention also encompasses certain pharmaceuticalcompositions and methods for treatment of cyclooxygenase-2 mediated diseases comprising the use of compounds of Formula I.

Description

BACKGROUND OF THE INVENTION

This invention relates to compounds and pharmaceutical compositions for treating cyclooxygenase-mediated diseases and methods of treatment therefor.

By inhibiting prostaglandin G/H synthase, also known as cyclooxygenase, nonsteroidal anti-inflammatory drugs exert most of their anti-inflammatory, analgesic and antipyretic effects and inhibit hormone-induced uterine contractions and certain types of carcinoma growth. Until recently, only one form of cyclooxygenase had been characterized, corresponding to cyclooxygenase-1 or the constitutive enzyme as originally identified in bovine seminal vesicles. Recently, the gene for a second, inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, mouse and human sources. This enzyme is distinct from cyclooxygenase-1, which has now also been cloned, sequenced and characterized from sheep, mouse and human sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and easily inducible by a variety of agents, including mitogens, endotoxin, hormones, cytokines, and growth factors. Since prostaglandins exert both physiological and pathological functions, we concluded that the constitutive enzyme, cyclooxygenase-1, is largely responsible for the endogenous basal release of prostaglandins and thus is important for their physiological functions, such as maintenance of gastrointestinal integrity or renal blood flow. In contrast, we concluded that the inducible form, cyclooxygenase-2, is primarily responsible for the pathological effects of prostaglandins, where rapid induction of the enzyme would occur in response to such agents as anti-inflammatory drugs, hormones, growth factors and cytokines. Thus, a selective cyclooxygenase-2 inhibitor will have similar anti-inflammatory, antipyretic and analgesic properties to a conventional non-steroidal anti-inflammatory drug and would additionally inhibit hormone-induced uterine contractions and have potential anticarcinogenic effects, but will have a reduced ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a reduced ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.

A number of stilbene derivatives are known in the chemical literature. Toda et al., Chem. Commun. 1234-5 (1984) describe the dialdehydes A, and diol B is described by Tsuji et al., J. Am. Chem. Soc. 88, 1289-92 (1966), and diol C was prepared by Dhawau et al., J. Org. Chem., 45, 922-4 (1980). These compounds are not disclosed as having any utility nor do they carry the R¹ substituent of the present invention.

A

X = H or Cl

B X = H Tsuji

C X = Cl Dhawan

Structure D is disclosed by Hashimoto et al., European Patent Application 424 541 (2 May 1991) as being useful for the treatment of hyperlipidemia.

X, Y are halogen

R is C1-6 alkyl

n is 0, 1 or 2

These compounds (D) lack the second carbon substituent X of the present invention and have an unrelated utility.

WO-A-950051 discloses phenyl-substituted heterocycles as cyclooxygenase-2 inhibitors.

US-A-5393790 discloses 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene as an intermediate in the preparation of phenyl-substituted spiro compounds suitable for ignition treatment.

SUMMARY OF THE INVENTION

The invention comprises novel compounds of formula I which are suitable for the treatment of cyclooxygenase-2-mediated diseases.

The invention also includes certain pharmaceutical compositions and methods for treating cyclooxygenase-2-mediated diseases which comprise the use of compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein

X

(a) CH₂OH,

(b) CHO,

(c) CO₂H or

(d) CO₂R�sup4;,

Y

(a) CH₂OH or

(b) CH₂OCOR�sup5;,

R¹ is selected from the group consisting of

(a) S(O)₂(O)CF₃,

(b) S(O)₂NH₂,

(c) S(O)₂NHC(O)CF₃,

(d) S(O)(NH)CH3,

(e) S(O)(NH)NH2,

(f) S(O)(NH)NHC(O)CF₃,

(g) P(O)(CH₃)OH and

(h) P(O)(CH₃)NH₂,

R² and R³ are each independently selected from the group consisting of

(a) hydrogen,

(b) halogens,

(c) C1-6 alkoxy,

(d) C1-6 alkylthio,

(e) CN,

(f) CF3,

(g) C1-6 alkyl,

(h) N₃,

R4 is selected from the group consisting of

(a) Hydrogen and

(b) C1-6 alkyl,

R&sup5; is selected from the group consisting of

(a) hydrogen,

(b) C1-6 alkyl,

(c) mono- or disubstituted phenyl, wherein the substituent is selected from

(1) Hydrogen,

(2) Halogens,

(3) C1-6 alkyl,

(4) C1-6 alkoxy,

(5) C1-6 alkylthio,

(6) OH,

(7) CN,

(8) CF₃ and

(9) CO₂R�sup4;,

with the proviso that the compound is other than 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene.

Preferred are compounds in which

X

(a) CH₂OH,

(b) CHO,

(c) CO₂H or

(d) CO₂R�sup4;,

Y

(a) CH₂OH or

(b) CH₂OCOR�sup5;,

R¹ is selected from the group consisting of

(a) S(O)₂CH₃,

(b) S(O)₂NH₂,

(c) S(O)₂NHC(O)CF₃,

(d) S(O)(NH)CH3,

(e) S(O)(NH)NH₂ and

(f) S(O)(NH)NHC(O)CF₃,

R² and R³ are each independently selected from the group consisting of

(a) hydrogen,

(b) fluorine, chlorine or bromine,

(c) C1-4 alkoxy,

(d) C1-4 alkylthio,

(e) CN,

(f) CF₃ and

(g) C1-4 alkyl,

R4 is selected from the group consisting of

(a) Hydrogen and

(b) C1-4 alkyl,

R&sup5; is selected from the group consisting of

(a) hydrogen,

(b) C1-4 alkyl,

(c) mono- or disubstituted phenyl, wherein the substituent is selected from

(1) Hydrogen,

(2) Halogens,

(3) C1-6 alkyl,

(4) C1-6 alkoxy,

(5) OH and

(6) CO₂R⁴.

Particularly preferred are compounds in which

X

(a) CH₂OH,

(b) CHO,

(c) CO₂H or

(d) CO₂R�sup4;,

Y CH2 OH or CH2 OCOR5 is,

R¹ is selected from the group consisting of

(a) S(O)₂CH₃,

(b) S(O)₂NH₂,

(c) S(O)₂NHC(O)CF₃,

(d) S(O)NHCH3,

(e) S(O)NHNH₂ and

(f) S(O)NHNHC(O)CF₃,

R² and R³ are each independently selected from the group consisting of

(1) Hydrogen,

(2) Fluorine, chlorine and bromine,

(3) C1-4 alkoxy,

(4) C1-4 alkylthio,

(5) CN,

(6) CF3,

(7) C1-4 alkyl and

(8) N3,

R4 is selected from the group consisting of

(a) Hydrogen and

(b) C1-4 alkyl,

R&sup5; is selected from the group consisting of

(a) hydrogen,

(b) C1-4 alkyl,

(c) mono- or disubstituted phenyl, wherein the substituent is selected from

(1) Hydrogen,

(2) Halogens,

(3) C1-6 alkyl,

(4) C1-6 alkoxy,

(5) OH,

(6) CO₂R⁴.

Particularly preferred are compounds in which

X

(a) CH₂OH,

(b) CHO or

(c) CO₂H,

Y CH2 OH or CH2 OCOR5 is,

R¹ is selected from the group consisting of

(a) S(O)₂CH₃,

(b) S(O)₂NH₂, and

(c) S(O)NHCH3,

(d) S(O)NHNH₂, and

R² and R³ are each independently selected from the group consisting of

(1) Hydrogen and

(2) fluorine, chlorine or bromine,

R4 is hydrogen and

R&sup5; is C1-3 alkyl.

Most preferred are compounds in which

X

(a) CH₂OH,

(b) CHO or

(c) CO₂H,

Y CH2 OH or CH2 OCOR5 is,

R¹ is selected from the group consisting of

(a) S(O)₂CH₃ and

(b) S(O)₂NH₂,

R² and R³ are each independently selected from the group consisting of

(1) Hydrogen and

(2) fluorine, chlorine or bromine,

R4 is hydrogen and

R&sup5; is C1-3 alkyl.

The invention also includes the novel compound of formula I as described above and 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene or pharmaceutically acceptable salts thereof which are suitable for the treatment of cyclooxygenase-2-mediated diseases

For the purposes of this specification, the definition of alkyl includes, among others, linear, branched and cyclic structures, with C₁₋₆ alkyl including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Similarly, C₁₋₆ alkoxy is intended to include alkoxy groups having 1 to 6 carbon atoms in straight, branched or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy. Similarly, C₁₋₆ alkylthio is intended to include alkylthio groups having 1 to 6 carbon atoms in straight, branched or cyclic configuration. Examples of lower alkylthio groups include, among others, Methylthio, propylthio, isopropylthio, cycloheptylthio. For example, the propylthio group denotes -SCH₂CH₂CH₃.

Some of the compounds described herein contain olefinic double bonds and, unless otherwise indicated, both the E and Z geometric isomers are intended to be included.

In a second embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase and treating cyclooxygenase-mediated diseases as disclosed herein, which comprise a pharmaceutically acceptable carrier and a nontoxic therapeutically effective amount of a compound of formula I as described above.

In this embodiment, the invention encompasses pharmaceutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein, the compositions comprising a pharmaceutically acceptable carrier and a nontoxic therapeutically effective amount of a compound of formula I as described above.

In a third embodiment, the invention comprises a method of inhibiting cyclooxygenase and treating cyclooxygenase-mediated diseases which are advantageously treated by an agent which, as disclosed herein, selectively inhibits COX-2 in preference to COX-1, comprising: administering a nontoxic therapeutically effective amount of a compound of formula I as disclosed herein to a patient in need of such treatment.

The pharmaceutical compositions of the present invention contain a compound of formula I as an active ingredient or a pharmaceutically acceptable salt thereof and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" means salts prepared from pharmaceutically acceptable non-toxic bases, including organic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese (III), manganese (II), potassium, sodium, zinc salts and the like. Especially preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as. B. Arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, idine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine.

It will be understood that in the following discussion of methods of treatment, reference to the compounds of formula I is intended to include also the pharmaceutically acceptable salts.

The compound of formula I is useful for relieving pain, fever and inflammation in a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, the common cold, lower back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, degenerative joint disease (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures. In addition, such a compound can inhibit neoplastic cell transformation and metastatic tumor growth and thus be used to treat cancer. The compounds of formula I can also be suitable for the treatment of dementia, including presenile and senile dementia, and in particular dementia associated with Alzheimer's disease (ie Alzheimer's dementia).

Compounds of formula I will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and may thus be useful in the treatment of dysmenorrhea, premature birth and asthma. They will also be useful in inhibiting bone loss (osteoporosis).

Due to their high cyclooxygenase-2 (COX-2) activity and/or their selectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1) as defined above, the compounds of formula I will prove to be a suitable alternative to conventional non-steroidal anti-inflammatory drugs (NSAs), particularly when such non-steroidal anti-inflammatory drugs may be contraindicated, such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or a history of recurrent gastrointestinal damage; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, hemophilia or other bleeding problems (including those involving reduced or impaired platelet function); renal disease (e.g. impaired renal function); in those who are about to undergo surgery or are taking anticoagulants, and in those who are susceptible to NSAID-induced asthma.

Similarly, compounds of formula I will be useful as a partial or complete replacement for conventional NSAIDs in preparations in which they are currently administered together with other agents or ingredients. Thus, in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above, which compositions comprise a non-toxic therapeutically effective amount of the compound of formula as defined above I and one or more ingredients such as another analgesic including acetominophen or phenacetin, a potentiator including caffeine, an H2 antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine or levodeoxyephedrine, a cough suppressant including codeine, hydrocodone, caramiphene, carbetapentane or dextramethorphan, a diuretic, a sedating or non-sedating antihistamine. Additionally, the invention encompasses a method of treating cyclooxygenase-mediated diseases comprising: administering to a patient in need of such treatment a nontoxic therapeutically effective amount of the compound of formula I, optionally administered together with one or more of the ingredients listed immediately above.

The compounds of the present invention are cyclooxygenase-2 inhibitors and are thereby useful in treating the cyclooxygenase-2 mediated diseases enumerated above. This effect is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-1. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase-mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. The IC50 values represent the inhibitor concentration required to restore PGE2 synthesis to 50% compared to that obtained with the uninhibited control. Illustrative of this aspect, we have found that the compounds of the examples inhibit COX-2 more than 100 times more effectively than they inhibit COX-1. In addition, they all have a COX-2 IC₅₀ value of 1 nM to 1 µM. For comparison, ibuprofen has a IC₅₀ for COX-2 of 1 µM and indomethacin has an IC₅₀ for COX-2 of about 100 µM. For the treatment of any of these cyclooxygenase-mediated diseases, the compound of formula I can be administered orally, topically, parenterally, by inhalation spray or rectally in unit dosage formulations containing conventional nontoxic pharmaceutically acceptable carriers, excipients and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intracisternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, the compound of the invention is effective for the treatment of humans.

As indicated above, pharmaceutical compositions for treating the defined cyclooxygenase-2-mediated diseases may optionally contain one or more of the ingredients listed above.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example as tablets, lozenges, medicinal tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavourings, colourings and preservatives to give pharmaceutically tasty and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate. Granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricants, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or coated by known methods to delay dissolution and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, a time delay material such as glycerol monostearate or glycerol distearate may be used. They may also be coated by the methods described in U.S. Patents 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredient in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate, The aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more colorants, one or more flavorings and one or more sweeteners, such as sucrose, saccharin or aspartame.

Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil, such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and flavorings can be added to give a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide the active ingredient in a mixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Additional excipients, for example sweeteners, flavourings and colourings, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifiers may be naturally occurring phosphatides, for example soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavourings.

Syrups and elixirs can be made with sweeteners, for example glycerin, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated in accordance with the known art using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. Any bland fixed oil may be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids, such as oleic acid, are used in the production of injectable preparations.

The compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at normal temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of formula I are used. (For the purposes of this application, topical application is intended to include mouthwashes and gargles.)

Dose concentrations in the range of 0.01 mg to 140 mg/kg body weight per day are appropriate in the treatment of the conditions specified above, or alternatively 0.5 mg to 7 g per patient per day. For example, inflammation may be effectively treated by the administration of 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively 0.5 mg to 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.

The amount of active ingredient that can be combined with the carrier materials to produce a unit dosage form will vary depending on the host being treated and the particular route of administration. For example, a formulation intended for oral administration to humans may contain 0.5 mg to 5 g of active ingredient compounded with an appropriate and convenient amount of carrier material, which may vary from 5 to 95% of the total composition. Unit dosage forms will generally contain between 1 mg and 500 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It will be understood, however, that the specific dose concentration for any particular patient will depend on a number of factors, including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition for which therapy is being administered.

Synthesis process

The compounds of the present invention can be prepared according to the following methods.

Method A:

A diphenyl lactone 2 is reduced to the diol 1a by a suitable reducing agent such as diisobutylaluminum hydride or lithium aluminum hydride in a suitable solvent such as toluene, hexane, tetrahydrofuran or ether. The diol is acylated with an anhydride or an acid chloride in the presence of a base such as pyridine, triethylamine or aqueous sodium hydroxide. This acylation gives the desired isomer 1b and the undesired isomer 3 which are separated by chromatography or crystallization. Compound 1b is oxidized to the aldehyde 1c by a reagent such as manganese dioxide. Mild acidic or basic hydrolysis of 1c gives 1d which is in equilibrium with the lactol form 4. Alternatively, 1c can be oxidized to the acid 1e with Cr⁺⁶ reagents. Treatment of 1e with base produces the salt 1f. The esters 1c can be prepared by reaction of 1e with an alkylating agent in the presence of a base. The methyl ester of 1e is conveniently prepared on a small scale by reaction of 1e with diazomethane in ether. PROCEDURE A CONTINUATION OF PROCEDURE A

Procedure AA:

A diphenylmaleic anhydride 18 can be reduced to the diol 1a with a suitable hydride reducing agent such as diisobutylaluminum hydride or lithium aluminum hydride. Solvents such as toluene, tetrahydrofuran or ether, or a mixture thereof, are suitable for the reduction. PROCEDURE AA

Lactones 2 are prepared by the following procedures.

Method B:

An appropriately substituted aryl bromomethyl ketone 5 is reacted with an appropriately substituted aryl acetic acid 6 in a solvent such as acetonitrile in the presence of a base such as triethylamine and then treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give the lactone 2. METHOD B

Procedure C

By reacting an acetylene 7 with carbon monoxide and water in the presence of suitable catalysts, a mixture of compound 2 and its isomer 8 is obtained. The isomers can be separated by standard techniques in the art such as chromatography or crystallization. Examples of suitable catalysts and conditions are PdCl₂ in aqueous HCl and EtOH heated to 50-150°C and at a pressure of 50-150 atmospheres, or Rh₄(COO)₁₂ (or Rh₆(CO)₁₆) in aqueous THF (or acetone, acetonitrile, benzene, toluene, EtOH, MeOH) containing trialkylamine at 50-150°C and 20-300 atmospheres pressure. See Takahashi et al., Organometallics 1991, 10, 2493-2498, and Tsuji et al., J. Am. Chem. Soc. 1966, 88, 1289-1292. METHOD C

Procedure D

1,4-Addition of 4-methylthiophenylorganometallic reagents 10 to 9 in the presence of copper salts and trapping of the resulting enolate with trialkylsilyl chloride such as TMSCl or TIPSCl gives the ketene acetal 11 . The ketene acetal can then be oxidized to the substituted butenolide 12 by the method of Ito using catalytic amounts of Pd2(OAc)2 and Cu(OAc)2 and O2 in MeOH or by the method of Magnus using PhIO/TMSN3 and Bu4NF. Introduction of the iodine can be accomplished by treatment of 13 with I2 in the presence of pyridine to give 13 . Palladium-catalyzed Suzuki or Stille coupling of 13 with the appropriate aryl partner such as phenyl ether provides the desired enolate. B. the boronic acid 14, gives the butenolide 15. The sulfide can be oxidized to a sulfone by various oxidizing agents, such as peracetic acid, MPPM, MMPP or H₂O₂, to give the desired compound 2a. See Y. Ito et al., J. Am. Chem. Soc. 1979, 101, 494, note 2, and P. Magnus et al., Tet. Lett. 1992, 2933. PROCEDURE D

Procedure E

The 2,3-diphenylmaleic anhydride 18 can be prepared by the process of Fields [J. Org. Chem., vol. 55, pp. 5165-70 (1990); US 4 596,867], in which phenylacetic acid 16 is reacted with an α-oxophenylacetic acid 17 (preferably as its potassium salt) in refluxing acetic anhydride.

A multistep sequence to 18 from phenylacetonitriles, such as 19 and 20, is described by Smith et al. in J. Org. Chem., volume 55, pages 3351-62 (1990).

Florac and co-workers describe in Tetrahedron, volume 46, pages 445-52 (1990), another synthesis of 18 in several steps from the α-bromophenylacetohydrazides 21 and 22.

Representative connections

In Table I are shown some lactones 2 from which the compounds of the present invention can be prepared according to Process A.

Representative compounds of the present invention are shown in Tables II and III (structures Ia and Ib). TABLE I TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE I (CONTINUED) TABLE II TABLE III

Tests to determine biological efficacy

The compound of formula T can be tested to determine its cyclooxygenase-2 inhibitory activity using the following tests.

Inhibition of cyclooxygenase action

The compounds are tested as inhibitors of cyclooxygenase action in whole-cell and microsomal cyclooxygenase assays. These two assays measure prostaglandin E2 (PGE2) synthesis in response to arachidonic acid using a radioimmunoassay. The cells used for the whole-cell assays and from which microsomes are prepared for microsomal assays are human osteosarcoma-143 cells (which specifically express cyclooxygenase-2) and human U-937 cells (which specifically express cyclooxygenase-1). In these assays, 100% activity is defined as the difference between prostaglandin E2 synthesis in the absence and in the presence of arachidonate addition. The IC50 values represent the concentration of putative inhibitor required to restore PGE2 synthesis to 50% compared to that obtained with the non-inhibited control.

Representative rat paw edema test - Protocol Male Sprague-Dawley rats (150-200 g) are fasted overnight and administered po at 9-10 a.m. either vehicle (5% Tween 80 or 1% Methocel) or test compound. One hour later, a line is drawn with a waterproof marker at the level above the ankle on one hind paw to mark the area of the paw to be monitored. Paw volume (V0h) is measured with a plethysmometer (Ugo-Basile, Italy) based on the principle of water displacement. Animals are then injected subplantarly with 50 μl of a 1% carrageenan solution in Saline (FMC Corp., Maine) is injected into the paw (i.e., 500 μg carrageenan per paw). Three hours later, paw volume (V3h) is measured and the increase in paw volume (V3h - V0h) is calculated. Animals are euthanized by CO2 aphyxiation and the absence or presence of gastric lesions are counted. Gastric counts are expressed as the sum of total lesions in mm. Paw edema data are compared with those of the vehicle control group and percent inhibition is calculated, taking values in the control group as 100%. All treatment groups are coded to exclude observer bias.

NSAID-induced gastropathy in rats Basics

The main side effect of conventional NSAIDs is their ability to produce gastric lesions in humans. This effect is thought to be caused by inhibition of COX-1 in the gastrointestinal tract. Rats are particularly sensitive to the effects of NSAIDs. In fact, rat models have been commonly used in the past to study the gastrointestinal side effects of current conventional NSAIDs. In the present test, NSAID-induced gastrointestinal damage is observed by measuring fecal 51Cr excretion following systemic injection of 51Cr-labeled red blood cells. Fecal 51Cr excretion is a well-established and sensitive method for assessing gastrointestinal integrity in animals and humans.

Proceedings

Male Sprague-Dawley rats (150-200 g) are administered a test compound orally either once (acute dosing) or BID for 5 days (chronic dosing). Immediately after the last dose, 0.5 ml of 5¹Cr-labeled red Blood cells from a donor rat are injected into a tail vein of the rats. Animals are placed individually in metabolism cages with food and water ad lib. Feces are collected over a 48-hour period and 51Cr fecal excretion is calculated as a percent of the total injected dose. 51Cr-labeled red blood cells are prepared by the following procedures. Ten ml of blood are collected through the vena cava from a donor rat into heparinized tubes. Plasma is removed by centrifugation and replaced with an equal volume of HBSS. Red blood cells are incubated with 400 uCi of sodium 51 chromate for 30 minutes at 37°C. At the end of incubation, red blood cells are washed twice with 20 ml of HBSS to remove free sodium 51 chromate. The red blood cells are finally taken up in 10 ml of HBSS, and 0.5 ml of the solution (about 20 uCi) is injected per rat.

Protein-losing gastropathy in squirrel monkeys Basics

Protein-losing gastropathy (evident by the appearance of circulating cells and plasma proteins in the GI tract) is a significant and dose-limiting adverse reaction to NSAIDs. This can be quantitatively assessed by intravenous administration of 5¹CrCl₃ solution. This isotopic ion can readily bind to cells and serum globins and to the endoplasmic reticulum of cells. Measurement of radioactivity appearing in feces collected up to 24 hours after administration of the isotope therefore provides a sensitive and quantitative indication of protein-losing gastropathy.

Proceedings

Groups of male squirrel monkeys (0.8 to 1.4 kg) are gavaged with either 1% Methocell or 5% Tween 80 in H₂O vehicles (3 ml/kg BID) or test compounds at doses of 1-100 mg/kg BID for 5 days. Intravenous ⁵5¹Cr (5 uCi/kg in 1 ml/kg PBS) is administered 1 hour after the last drug/vehicle dose and feces are collected in a metabolism cage for 24 hours and analyzed for excreted ⁵5¹Cr by gamma counting. Venous blood samples are taken 1 hour and 8 hours after the last drug dose and plasma drug concentration is measured by RP-HPLC.

The invention will now be illustrated by the following non-limiting examples in which, unless otherwise stated:

(i) all experiments were carried out at room or ambient temperature, i.e. at a temperature in the range 18-25ºC; evaporation of the solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals: 4.5-30 mm Hg) at a bath temperature of up to 60ºC; the course of the reaction was followed by thin layer chromatography (TLC) and reaction times are given for illustrative purposes only; melting points are uncorrected and "dec." means decomposition; melting points given are those obtained for materials prepared as described; polymorphism in some preparations may lead to the isolation of materials with different melting points; the structure and purity of all final products was assured by at least one of the following methods: TLC, mass spectroscopy, nuclear magnetic resonance spectroscopy (MIR) or microanalytical data; yields are given for illustrative purposes only; MIR data, when given, in the form of delta (δ) values for major protons important for the determination in parts per million parts (ppm) relative to tetramethylsilane (TMS) as an internal standard, recorded at 300 MHz or 400 MHz using the solvent indicated; conventional abbreviations used for the signal shape are: s singlet, d doublet, t triplet, m multiplet, br. broad, etc., and further "Ar" denotes an aromatic signal; chemical symbols have their usual meanings; the following abbreviations have also been used: vol. (volume), wt. (weight), bp. (boiling point), mp. (melting point), 1 (liter), ml (milliliter), g (gram), mg (milligram), mol (moles), mmol (millimoles), eq. (equivalent(s)).

The following abbreviations have the meanings indicated:

Ac = Acetyl

Bn = benzyl

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

DIBAL = Diisobutylaluminum hydride

DMAP = 4-(dimethylamino)pyridine

DMF = N,N-dimethylformamide

Et₃N = triethylamine

HBSS = Hank's Matched Salt Solution

LDA = lithium diisopropylamide

m-CPBA = metachloroperbenzoic acid

MMPP = monoperoxyphthalic acid

MPPM = monoperoxyphthalic acid magnesium salt · 6H₂O

MS = methanesulfonyl = mesyl = SO2 Me

MsO = methanesulfonate = mesylate

NSAID = non-steroidal anti-inflammatory drug

OXONE® = 2KHSO5 · KHSO&sub9; · K&sub2;SO&sub4;

PBS = phosphate buffered saline

PCC = pyridinium chlorochromate

PDC = pyridinium dichromate

Ph = Phenyl

Phe = benzenediyl

Pye = pyridinediyl

RT = room temperature

rac. = racemic

SAM = aminosulfonyl or sulfonamide or SO₂NH₂

TBAF = Tetra-n-butylammonium fluoride

Th = 2- or 3-thienyl

TFAA = trifluoroacetic anhydride

THF = Tetrahydrofuran

Thi = thiophenediyl

DC = thin layer chromatography

TMS-CN = trimethylsilyl cyanide

Tz = 1H(or 2H)-tetrazol-5-yl

C₃H₅ = Allyl

Alkyl group abbreviations

Me = Methyl

Et = Ethyl

n-Pr = Normalpropyl

i-Pr = Isopropyl

n-Bu = Normalbutyl

i-Bu = isobutyl

s-Bu = secondary butyl

t-Bu = tertiary butyl

c-Pr = Cyclopropyl

c-Bu = cyclobutyl

c-Pen = Cyclopentyl

c-Hex = Cyclohexyl

EXAMPLE 1 (Z)-2-(4-(METHYLSULFONYL)PHENYL)-3-PHENYL-2-BUTENE-1,4-DIOL

To a solution of DIBAL (75 mL, 1M in toluene) cooled to 0 °C was added dropwise a solution of lactone 1 (5.0 g in 200 mL of THF). After stirring for 30 min at 0 °C and 30 min at RT, the mixture was then transferred with a double-pointed needle to 200 mL of 1M sodium potassium tartrate containing 50 mL of MeOH. The product was extracted with EtOAc (200 mL) and dried over MgSO4. Filtration and concentration gave the title compound (5.0 g) as a colorless syrup.

Alternative manufacturing

To a mixture of 3.28 g (10 mmol) of anhydride 1 and 200 mL of Et2O is added 0.76 g (20 mmol) of LiAlH4. The addition is carried out portionwise over a period of 20 min while the reaction mixture is stirred vigorously at RT. After an additional 30 min, 1 N HCl is added, the layers are separated and the aqueous layer is extracted with 200 mL of Et2O. The combined Et2O extracts are dried (MgSO4), evaporated and the residue is chromatographed to give the title compound.

EXAMPLE 2 (Z)-2-(4-(METHYLSULFONYL)PHENYL)-3-PHENYL-2-BUTENE-1,4-DIOL-1-ACETATE

A solution of 2-(4-(methylsulfonyl)phenyl)-3-phenyl-2-butene-1,4-diol (149 mg) and Et3N (0.2 mL) in 20 mL of CH2Cl2 was treated with Ac2O (0.05 mL) and DMAP (5 mg). After stirring for 10 min at RT, the mixture was concentrated and the residue was purified by flash chromatography using 3:2 EtOAc/hexane as eluent to give 40 mg of the title compound as a white solid together with 30 mg of its regioisomer as a syrup.

1 H-NMR (acetone-d6 ) ? 7.70 (2H, d), 7.32 (2H, d), 7.05-7.12 (5H, m), 5.71 (2H, s), 4.62 (2H, d), 4.06 (1H, t), 3.05 (3H, s), 1.93 (3H, s).

EXAMPLE 3 (Z)-4-ACETOXY-3-(4-(METHYLSULFONYL)PHENYL)-2-PHENYL-2-BUTENAL

A mixture of the acetate from Example 2 (215 mg) and MnO2 (1.2 g) in 30 mL of CH2Cl2 was stirred at RT for 12 h and then filtered through a pad of celite. The filtrate was concentrated to give 160 mg of the title compound as a yellow solid.

1 H-NMR (acetone-d6 ) ? 10.50 (1H, s), 7.78 (2H, d), 7.46 (2H, d), 7.16 (3H, m), 6.98 (2H, m), 5.60 (2H , s), 3.06 (3H, s), 1.93 (3H, s).

EXAMPLE 4 (Z)-4-ACETOXY-3-(4-(METHYLSULFONYL)PHENYL)-2-PHENYL-2-BUTENIC ACID

To a solution of the aldehyde from Example 3 (160 mg) and 2-methyl-2-butene (6 mL) in 2-methyl-2-propanol (35 mL) was added a solution of NaClO2 (1 g) and NaH2PO4 (1 g) in 10 mL H2O. The mixture was stirred at RT for 2 h and concentrated. The residue was then taken up in 50 mL of pH 7 buffer solution (1M) and extracted with EtOAc (50 mL). The extract was dried over MgSO4 and concentrated. The residue was purified by flash chromatography using 3:1 EtOAc/hexane containing 1% HOAc as eluant to give 150 mg of the title compound as a white solid.

1 H-NMR (acetone-d6 ) ? 7.77 (2H, d), 7.43 (2H, d), 7.10-7.20 (5H, m), 5.25 (2H, s), 3.06 (3H, s), 2 .60-3.00 (1H, br. s), 1.89 (3H, s).

EXAMPLE 5 (Z)-4-ACETOXY-3-(4-(METHYLSULFONYL)PHENYL)-2-PHENYL-2-BUTENEIC ACID METHYL ESTER

To a suspension of the acid from Example 4 (100 mg) in Et2O (20 mL) was added dropwise an excess of CH2N2 solution in Et2O. The solution was concentrated and the solid was swirled with 2:1 hexane/EtOAc to give 90 mg of the title compound as a white solid.

1 H-NMR (acetone-d6 ) ? 7.79 (2H, d), 7.44 (2H, d), 7.17 (3H, m), 7.08 (2H, m), 5.17 (2H, s), 3.80 (3H , s), 3.06 (3H, s), 1.90 (3H, s).

PRODUCTION OF MALEIC ACID ANHYDRIDE INTERMEDIATES ANHYDRIDE 1 2-(4-(Methylsulfonyl)phenyl)-3-phenylmaleic anhydride

A mixture of 21.4 g (0.10 mol) of 4-(methylsulfonyl)phenylacetic acid [Forrest et al., J. Chem. Soc. (1948), 1501-1506] and 18.8 g (0.10 mol) of potassium benzoylformate in 200 mL of Ac₂O is stirred and refluxed for 2 h. The reaction mixture is cooled to RT and poured into 1 L of H₂O and stirred until the Ac₂O dissolves (ca. 2 h). The precipitate is filtered off and dried to give the title compound. If desired, it is recrystallized from HOAc or acetone.

PRODUCTION OF LACTONE INTERMEDIATES LACTONE 1 PRODUCTION A 3-Phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of phenylacetic acid (27.4 g, 201 mmol) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (lactone 11, step 1) (60 g, 216 mmol, 1.075 equiv) in acetonitrile (630 mL) at 25 °C was slowly added Et3N (30.8 mL, 1.1 equiv). The mixture was stirred at RT for 20 min and then cooled in an ice bath. DBU (60.1 mL, 3 equiv) was slowly added. After stirring in the ice bath for 20 min, the reaction was complete and the mixture was acidified with 1 N HCl (color change from dark brown to yellow). Then 2.4 L of ice and H2O were added, stirred for a few minutes, then the precipitate was filtered and rinsed with H2O (to give 64 g of crude wet product). The solid was dissolved in 750 mL of CH2Cl2, dried over MgSO4, filtered and 300 mg of silica gel was added. The solvent was evaporated to near dryness (silica gel, slightly sticky) and the residue was added to the top of a plug of silica gel in a sintered glass funnel and eluted with 10% EtOAc/CH2Cl2 to give 36.6 g (58%) of the title compound after evaporation of the solvent and swirling in EtOAc.

Analysis calculated for C₁₇H₁₄O₄S

C, 64.95; H, 4.49; S, 10.20

Found: C, 64.63; H, 4.65; S, 10.44

PRODUCTION B 3-Phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 g of 2-(4-(methylsulfonyl)phenyl)phenylacetylene, 20 mg of Rh₄(CO)₁₂, 1.5 g of Et₃N, 10 mL of THF and 1 mL of H₂O are added to a 20 mL glass vial under a nitrogen atmosphere and the vial is placed in a 100 mL stainless steel autoclave. The reaction system is flushed three times with CO, then brought to an initial CO pressure of 100 atm at RT. The reaction is kept at 100 °C for 5 hours. The solution is then diluted with 50 mL of benzene and washed with brine and 1 N HCl. The Benzene solution is dried over Na₂SO₄ and concentrated. The crude products are purified by column chromatography on silica gel with 2:1 EtOAc/hexane as eluent to give the title compound and its regioisomer.

PRODUCTION C 3-Phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone Step 1: 2-Trimethylsilyloxy-4-(4-(methylthio)phenyl)-3,4-dihydrofuran

To a solution of 3.86 g (19 mmol) of 4-bromothioanisole in 90 mL of Et2O cooled to -78°C, 22 mL of a 1.7M solution of t-BuLi in pentane (38 mmol) is added dropwise. The reaction mixture is stirred at -78°C for 15 min, 3.8 g of CuI is added and the reaction mixture is allowed to warm to -40°C over a period of 30 min. A solution of 1.7 g of 2(5H)-furanone in 10 mL of THF is added. After stirring for 1 h, 2 mL of freshly distilled TMSCl is added dropwise. The reaction mixture is then saturated with 2 mL of Et3 N and 50 mL of NaHCO3 and extracted with 100 mL of Et2O. The Et2O layer is dried over Na2SO4 and concentrated to give the crude title compound, which is used in the next step without further purification.

Step 2 : 4-(4-(Methylthio)phenyl)-2-(5H)-furanone

To a solution of 4 g of Pd(OAc)2 in 100 mL of acetonitrile is added dropwise the crude product from step 1 (5 g) under nitrogen at RT. After 10 hours at RT, the mixture is concentrated by evaporation and the residue is purified by flash chromatography on silica gel using 2:1 hexane/EtOAc as eluant to give the title compound.

Step 3 : 3-Iodo-4-(4-(methylthio)phenyl)-2-(5H)-furanone

To a solution of 3 g of the product from step 2 in 30 mL of pyridine is added 8.7 g of I2. The mixture is stirred for 24 h and then diluted with 200 mL of Et2O, washed with 100 mL of 5N HCl and with 50 mL of 5N Na2S2O3. The Et2O layer is dried over Na2SO4 and concentrated to give the title compound.

Step 4 : 3-Phenyl-4-(4-(methylthio)phenyl)-2-(5H)-furanone

A mixture of 4 g of the product from step 3, 3.7 g of PhB(OH)2, 0.4 g of Ph3As, 0.4 g of PdCl2(PhCN)2 in 100 mL of benzene and 15 mL of 2 N NaOH is refluxed for 6 h. Then Et2O (200 mL) is added and the mixture is washed with 100 mL of saturated NaHCO3. The organic layer is dried over MgSO4 and concentrated. The residue is purified by flash chromatography on silica gel using 4:1 hexane/EtOAc as eluant to give the title compound.

Step 5: 3-Phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of 3 g of the product from step 4 in 80 mL of 10:1 CH2Cl2/MeOH was added 5.5 g of MPPM. The reaction mixture was stirred at RT for 2 h, then diluted with 100 mL of 1:1 hexane/EtOAc. After filtration and concentration, the residue was purified by flash chromatography using 2:1 EtOAc/hexane as eluent to give the title product.

LACTONE 2 3-(4-Fluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (CD3 COCD3 ) ? 5.34 (2H, s), 6.67 (2H, br. d), 7.18 (2H, m), 7.46 (2H, m), 7.61 (2H, m), 7.90 (2H, m).

Melting point: 187-188ºC (decomposition).

LACTONE 3 3-(2,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂F₂O₄S

C, 58.28; H, 3.45; S, 9.15

Found: C, 58.27; H, 3.50; S, 9.27

LACTONE 4 3-(3,4-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

To a solution of 3,4-difluorophenylacetic acid (ALDRICH CHEMICAL) (10 g) and 2-bromo-1-(4-(methylsulfonyl)phenyl)ethanone (lactone 11, step 1) (17.3 g) in acetonitrile (200 mL) at RT was slowly added ET3N (20.2 mL). After 1 h at RT, the mixture was cooled in an ice bath and treated with 17.4 mL of DBU. After 2 h at 0 °C, the mixture was treated with 200 mL of 1 N HCi and the product was extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was applied to the top of a plug of silica gel in a sintered glass funnel, eluted with 75% EtOAc/hexane to give 10 g of the title compound after evaporation of the solvent and swirling in EtOAc.

Analysis calculated for C₁₇H₁₂F₂O₄S

C, 58.28; H, 3.45; S, 9.15

Found: C, 58.02; H, 3.51; S, 9.35

LACTONE 5 3-(2,6-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂F₂O₄S

C, 58.28; H, 3.45; S, 9.15

Found: C, 58.18; H, 3.50; S, 9.44

LACTONE 6 3-(2,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂F₂O₄S

C, 58.28; H, 3.45; S, 9.15

Found: C, 58.89; H, 3.51; S, 9.11

LACTONE 7 3-(3,5-Difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂F₂O₄S

C, 58.28; H, 3.45; S, 9.15

Found: C, 58.27; H, 3.62; S, 9.32

LACTONE 8 3-(4-Bromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₃BrO₄S

C, 51.94; H, 3.33; S, 8.16

Found: C, 51.76; H, 3.42; S, 8.21

LACTONE 9 3-(4-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl-2-(5H)-furanone

1 H-NMR (300 MHz, CDCl3 ) ? 7.93 (2H, d), 7.49 (2H, d), 7.35 (4H, m), 5.16 (2H, s), 3.06, (3H, s).

LACTONE 10 4-(4-Methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈₋H₁₆O₅S

C, 62.78; H, 4.68; S, 9.31

Found: C, 62.75; H, 4.72; S, 9.39

LACTONE 11 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone Step 1 : 2-Bromo-1-(4-(methylsulfonyl)phenyl)ethanone

To a solution of 197 g of 4-(methylthio)acetophenone (ref: JACS, 1952, 74, p. 5475) in 700 mL of MeOH and 3500 mL of CH2Cl2 was added 881 g of MMPP over a period of 30 min. After 3 h at RT, the reaction mixture was filtered and the filtrate washed with 2 L of saturated aqueous NaHCO3 solution and 1 L of brine. The aqueous phase was further extracted with 2 L of CH2Cl2. The combined extracts were dried over Na2SO4, concentrated to give 240 g of 4-(methylsulfonyl)acetophenone as a white solid.

To a cooled (-5 °C) solution of 174 g of 4-(methylsulfonyl)acetophenone in 2.5 L of CHCl3 was added 20 mg of AlCl3, followed by a solution of 40 mL of Br2 in 300 mL of CHCl3. The reaction mixture was then treated with 1.5 L of H2O and the CHCl3 was separated. The aqueous layer was extracted with 1 L of EtOAc. The combined extracts were dried over Na2SO4 and concentrated. The crude product was recrystallized from 50/50 EtOAc/hexane to give 210 g of the title compound as a white solid.

Step 2:

To the product from step 1 (216 mg) dissolved in acetonitrile (4 After the reaction mixture was dissolved in 100 ml of ethyl acetate (30% EtOAc in hexane), Et3N (0.26 ml) was added, followed by 4-fluorophenylacetic acid (102 mg). After 1.5 h at rt, 0.23 ml of DBU was added. The reaction mixture was stirred for an additional 45 min and then treated with 5 ml of 1 N HCl. The product was extracted with EtOAc, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (40% EtOAc in hexane) to give 150 mg of the title compound as a solid.

1 H-NMR (CD3 COCD3 ) ? 3.15 (3H, s), 5.36 (3H, s), 7.18 (2H, J = 8.9 Hz, t), 7.46 (2H, m), 7.7 (2H, J = 8.65 Hz, d), 7.97 (2H, J = 8.68, d).

LACTONE 12 3-(2-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₃ClO₄S

C, 58.54; H, 3.76; S, 9.19

Found: C, 58.59; H, 3.80; S, 9.37

LACTONE 13 3-(2-Bromo-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂BrFO₄S

C, 49.75; H, 2.93

Found: C, 49.75; H, 3.01

LACTONE 14 3-(2-Bromo-4-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, acetone-d6 ) ? 7.95 (2H, d), 7.85 (1H, d), 7.63 (2H, dd), 7.55 (1H, dd), 7.45 (1H, d), 5.50 (2H, s), 3.15 (3H, s)

LACTONE 15 3-(4-Chloro-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, acetone-d6 ) ? 8.0 (2H, d), 7.70 (2H, d), 7.50-7.30 (3H, m), 5.35 (2H, s), 3.15 (3H, s)

LACTONE 16 3-(3-Bromo-4-fluorophenyl)-4-(4-(methylsulfonylYohenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂BrFO₄S

C, 49.75; H, 2.93

Found: C, 49.44; H, 2.98

LACTONE 17 3-(3-Chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₃ClO₄S

C, 58.54; H, 3.76

Found: C, 58.29; H, 3.76

LACTONE 18 3-(2-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂ClFO₄S

C, 55.67; H, 3.30

Found: C, 55.67; H, 3.26

LACTONE 19 3-(2,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂Cl₂O₄S

C, 53.28; H, 3.16; S, 8.37

Found: C, 52.89; H, 3.23; S, 8.58

LACTONE 20 3-(3,4-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂Cl₂O₄S

C, 53.28; H, 3.16; S, 8.37

Found: C, 53.07; H, 3.32; S, 8.51

LACTONE 21 3-(2,6-Dichlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂Cl₂O₄S

C, 53.28; H, 3.16; S, 8.37

Found: C, 52.99; H, 3.22; S, 8.54

LACTONE 22 3-(3-Chloro-4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, acetone-d6 ) ? 8.0 (2H, d), 7.70 (2H, d), 7.60 (1H, d), 7.25-7.40 (2H, m), 5.35 (2H, s), 3.15 (3H, s)

LACTONE 23 3-(4-Trifluoromethylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (CD3 COCD3 ) ? 8.10 (2H, d), 7.82-7.93 (4H, m), 7.75 (2H, d), 5.55 (2H, s), 3.30 (3H, s)

LACTONE 24 3-(3-Fluoro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈₋H₁₅FO₅S

C, 59.66; H, 4.17

Found: C, 59.92; H, 4.37

LACTONE 25 3-(3-Chloro-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈₋H₁₅ClO₅S

C, 57.07; H, 3.99

Found: C, 57.29; H, 4.15

LACTONE 26 3-(3-Bromo-4-methoxyphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈₋H₁₅BrO₅S

C, 51.08; H, 3.57

Found: C, 51.38; H, 3.62

LACTONE 27 3-(2-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₃FO₄S

C, 61.44; H, 3.94

Found: C, 61.13; H, 3.85

LACTONE 28 3-(4-Methylthiophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, acetone-d6 ) ? 8.0 (2H, d), 7.70 (2H, d), 7.35 (2H, d), 7.25 (2H, d), 5.35 (2H, s), 3.15 (3H , s), 2.55 (3H, s)

LACTONE 29 3-(3-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, CDCl3 ) ? 7.93 (2H, d), 7.49 (2H, d), 7.35 (1H, m), 7.12 (3H, m), 5.18 (2H, s), 3.06 (3H , s)

LACTONE 30 3-12-Chloro-6-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, acetone-d6 ) ? 8.0 (2H, d), 7.70 (2H, d), 7.55-7.65 (1H, m), 7.40 (1H, d), 7.30 (1H, m), 5 .60 (2H, s), 3.15 (3H, s)

LACTONE 31 3-(3-Bromo-4-methylphenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₈₋H₁₅BrO₄S

C, 53.08; H, 3.71

Found: C, 53.06; H, 3.83

LACTONE 32 3-(4-Bromo-2-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂BrFO₄S

C, 49.65; H, 2.94

Found: C, 49.76; H, 3.00

LACTONE 33 3-(3,4-Dibromophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (300 MHz, acetone-d6 ) ? 8.0 (2H, d), 7.80 (1H, d), 7.75 (3H, m), 7.25 (1H, d), 5.35 (2H, s), 3.15 (sH , s)

LACTONE 34 3-(4-Chloro-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂ClFO₄S

C, 55.67; H, 3.30

Found: C, 55.45; H, 3.30

LACTONE 35 3-(4-Bromo-3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂BrFO₄S

C, 49.66; H, 2.94; S, 7.80

Found: C, 49.79; H, 3.01; S, 7.51

LACTONE 36 3-(4-Bromo-2-chlorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₂BrClO₄S

C, 47.74; H, 2.83; S, 7.50

Found: C, 47.92; H, 2.84; S, 7.42

LACTONE 37 3-(3,4-Dichlorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (400 MHz, CD3 COCD3 ) ? 7.92 (2H, dd), 7.64 (3H, dm), 7.60 (1H, dd), 7.32 (1H, dd), 6.70 (1H, br. s), 5.38 (2H, s)

LACTONE 38 3-(3,4-Difluorophenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone

1 H-NMR (400 MHz, CD3 COCD3 ) ? 7.92 (2H, dd), 7.64 (2H, dd), 7.30-7.45 (2H, m), 7.22 (1H, m), 6.68 (2H, br. s) , 5.37 (2H, s)

LACTONE 39 3-(3-Chloro-4-methoxyphenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₄ClNO₅S

C, 53.76; H, 3.72; N, 3.69

Found: C, 53.32; H, 3.84; N, 3.59

MS (DCI, CH₄) calcd for M⁺, 379

Found for M+ + 1, 380

LACTONE 40 3-(3-Bromo-4-methoxyphenyl)-4-(4-(aminosulfonyl)phenyl)-2-(5H)-furanone

Analysis calculated for C₁₇H₁₄BrNO₅S

C, 48.13; H, 3.33; N, 3.30

Found: C, 48.26; H, 3.40; N, 3.28

MS (DCI, CH₄) calcd for M⁺, 423

Found for M+ + 1, 424

EXAMPLE 6 (Compound 10) (Z)-2-(4-(METHYLSULFONYL)PHENYL)-3-(3,4-DIFLUOROPHENYL)-2-BUTENE-1,4-DIOL

A solution of DIBAL (185 ml, 1M in toluene) was added dropwise to a solution of lactone 4 (20 g in 800 ml THF) at 0 °C. After stirring at 0 °C for 90 min and at RT for 18 h, the mixture was again cooled to 0 °C and 100 ml of 1M sodium potassium tartrate was added dropwise. The product was extracted with ethyl acetate (200 ml) and dried over MgSO4. The Filtration and concentration gave the title compound (20 g) as a colorless syrup.

1 H-NMR (acetone-d6 ) ? 7.73 (2H, d), 7.38 (2H, d), 7.05 (2H, m), 6.85 (1H, m), 4.60 (4H, d), 4.10 (2H , br.), 3.05 (3H, s).

EXAMPLE 7 (Compound 11) (Z)-2-(4-(METHYLSULFONYL)PHENYL)-3-(3,4-DIFLUOROPHENYL)-2-BUTENE-1,4-DIOL-1-ACETATE

A solution of acetyl chloride (4.8 g) in CH2Cl2 (10 mL) was added dropwise to a solution of the diol from Example 10 (21.6 g), Et3N (17.4 mL) and DMAP (1.0 g) in CH2Cl2 (2.0 L) at 0 °C. After stirring for 15 min, 1 N HCl (300 mL) was added and the organic layer was separated, dried over MgSO4 and concentrated. The residue was purified by flash chromatography with 1:1 EtOAc/toluene to give 5.9 g of the title compound as a syrup followed by 5.9 g of its regioisomer as a syrup.

1 H-NMR (acetone-d6 ) ? 7.75 (2H, d), 7.37 (2H, d), 7.10 (2H, m), 6.85 (1H, m), 5.18 (2H, s), 4.62 (2H , d), 4.15 (1H, t), 3.05 (3H, s), 1.93 (3H, s).

EXAMPLE 8 (Compound 12) (Z)-4-ACETOXY-3-(4-(METHYLSULFONYL)PHENYL)-2-(3,4-DIFLUORPHENYL)-2-BUTENAL

A mixture of the acetate from Example 11 (5.4 g) and MnO2 (4.3 g) in EtOAc was stirred at RT for 18 h and then filtered through a pad of celite. The filtrate was concentrated to give 3.6 g of the title compound as a yellow syrup.

1 H-NMR (acetone -d6 ) ? 10.52 (1H, s), 7.85 (2H, d), 7.52 (2H, d), 7.10 (2H, m), 6.78 (1H, m), 5.63 (2H , s), 3.05 (3H, s), 1.95 (3H, s).

EXAMPLE 9 (Compound 13a) (Z)-4-ACETOXY-3-(4-METHYLSULFONYL)PHENYL)-2-(3,4-DIFLUORPHENYL)-2- BUTENEIC ACID

To a solution of the aldehyde from Example 12 (3.6 g), 2-methyl-2-butene (36 mL), THF (54 mL), and t-BuOH (180 mL) was added a solution of NaClO2 (7.3 g) and NaH2PO4 (8.6 g) in 1120 (108 mL). The mixture was stirred at RT for 1 h. The upper organic layer was separated and concentrated. The residue was redissolved in EtOAc (50 mL), dried over MgSO4, filtered, and reconcentrated. The residue was purified by flash chromatography with 1:1 EtOAc/hexane containing 5% acetic acid to give 1.3 g of the title compound, mp 133-134 °C.

Analysis calculated for C₁�9H₁₆F₂SO₆

C, 55.60; H, 3.92; F, 9.25; S, 7.81

Found: C, 55.31; H, 4.00; F, 8.86; S, 8.04

EXAMPLE 10 (Compound 13b) (Z)-4-ACETOXY-3-(4-(METHYLSULFONYL)PHENYL)-2-(3,4-DIFLUORPHENYL)-2- BUTENIC ACID SODIUM SALT

A mixture of the acid from Example 13a (1.18 g), NaHCO₃ (243 mg) and H₂O (75 ml) was ultrasonicated for 30 minutes and filtered through a sintered glass funnel to obtain a clear solution. The solution was frozen and freeze-dried to give 1.1 g of the title compound as a white powder.

1 H-NMR (DMSO-d6 ) ? 7.68 (2H, d), 7.28 (2H, d), 7.20 (1H, m), 7.10 (1H, m), 6.68 (1H, m), 5.08 (2H , s), 3.15 (3H, s), 1.85 (3H, s).

Claims (14)

1. A compound of formula I or pharmaceutically acceptable salts thereof, wherein X (a) CO₂OH , (b) CHO, (c) CO₂H or (d) CO₂R�sup4;, Y (a) CH₂OH or (b) CH₂OCOR�sup5;, R¹ is selected from the group consisting of (a) S(O)₂CH₃, (b) S(O)₂NH₂, (c) S(O)₂NHC(O)CF₃, (d) S(O)(NH)CH3, (e) S(O)(NH)NH2, (f) S(O)(NH)NHC(O)CF₃, (g) P(O)(CH₃)OH and (h) P(O)(CH₃)NH₂, R² and R³ are each independently selected from the group consisting of (a) hydrogen, (b) halogens, (c) C1-6 alkoxy, (d) C1-6 alkylthio, (e) CN, (f) CF3, (g) C1-6 alkyl, (h) N₃, R4 is selected from the group consisting of (a) Hydrogen and (b) C1-6 alkyl, R&sup5; is selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) mono- or disubstituted phenyl, wherein the substituent is selected from (1) Hydrogen, (2) Halogens, (3) C1-6 alkyl, (4) C1-6 alkoxy, (5) C1-6 alkylthio, (6) OH, (7) CN, (8) CF₃ and (9) CO₂R�sup4;, with the proviso that the compound is other than 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene. 2. A compound according to claim 1, wherein X (a) CH₂OH, (b) CHO, (c) CO₂H or (d) CO₂R�sup4;, Y (a) CH₂OH or (b) CH₂OCOR�sup5;, R¹ is selected from the group consisting of (a) S(O)₂CH₃, (b) S(O)₂NH₂, (c) S(O)₂NHC(O)CF₃, (d) S(O)(NH)CH3, (e) S(O)(NH)NH₂ and (f) S(O)(NH)NHC(O)CF₃, R² and R³ are each independently selected from the group consisting of (a) hydrogen, (b) fluorine, chlorine or bromine, (c) C1-4 alkoxy, (d) C1-4 alkylthio, (e) CN, (f) CF₃ and (9) C1-4 alkyl, R4 is selected from the group consisting of (a) Hydrogen and (b) C1-4 alkyl, R&sup5; is selected from the group consisting of (a) hydrogen, (b) C₁₄alkyl, (c) mono- or disubstituted phenyl, wherein the substituent is selected from (1) Hydrogen, (2) Halogens, (3) C1-6 alkyl, (4) C1-6 alkoxy, (5) OH and (6) CO₂R⁴. 3. A compound according to claim 2, wherein: X (a) CH₂OH, (b) CHO, (c) CO₂H or (d) CO₂R�sup4;, Y CH2 OH or CH2 OCOR5 is, R¹ is selected from the group consisting of (a) S(O)₂CH₃, (b) S(O)₂NH₂, (c) S(O)₂NHC(O)CF₃, (d) S(O)NHCH3, (e) S(O)NHNH₂ and (f) S(O)NHNHC(O)CF₃, R² and R³ are each independently selected from the group consisting of (1) Hydrogen, (2) Fluorine, chlorine and bromine, (3) C1-4 alkoxy, (4) C1-4 alkylthio, (5) CN, (6) CF3, (7) C1-4 alkyl and (8) N3, R4 is selected from the group consisting of (a) Hydrogen and (b) C1-4 alkyl, R&sup5; is selected from the group consisting of (a) hydrogen, (b) C1-4 alkyl, (c) mono- or disubstituted phenyl, wherein the substituent is selected from (1) Hydrogen, (2) Halogens, (3) C1-6 alkyl, (4) C1-6 alkoxy, (5) OH, (6) CO₂R⁴. 4. A compound according to claim 3, wherein: X (a) CH₂OH, (b) CHO or (c) CO₂H, Y CH2 OH or CH2 OCOR5 is, R¹ is selected from the group consisting of (a) S(O)₂CH₃, (b) S(O)₂NH₂, (c) S(O)NHCH3, (d) S(O)NHNH₂, and R² and R³ are each independently selected from the group consisting of (1) Hydrogen and (2) fluorine, chlorine or bromine, R4 is hydrogen and R&sup5; C1-3 alkyl. 5. A compound according to claim 4, wherein: X (a) CH₂OH, (b) CHO or (c) CO₂H, Y CH2 OH or CH2 OCOR5 is, R¹ is selected from the group consisting of (a) S(O)₂CH₃ and (b) S(O)₂NH₂, R² and R³ are each independently selected from the group consisting of (1) Hydrogen and (2) fluorine, chlorine or bromine, R4 is hydrogen and R&sup5; C1-3 alkyl. 6. A compound according to claim 1, wherein: X is CO₂R�sup4, Y is CH₂OCOR�sup5; R¹ is S(O)₂CH₃, R² and R³ are each independently selected from the group consisting of (a) Hydrogen and (b) halogens, R4 is selected from the group consisting of (a) Hydrogen and (b) C1-6 alkyl, R&sup5; is selected from the group consisting of (a) C1-6 alkyl and (b) mono- or disubstituted phenyl, wherein the substituent is selected from (1) Hydrogen, (2) Halogens, (3) C1-6 alkoxy, (4) OH. 7. A compound according to claim 1 selected from the group consisting of (a) (Z)-2-(4-(Methylsulfonyl)phenyl)-3-phenyl-2-butene-1,4-diol, (b) (Z)-2-(4-(Methylsulfonyl)phenyl)-3-phenyl-2-butene-1,4-diol-1-acetate, (c) (Z)-4-Acetoxy-3-(4-(methylsulfonyl)phenyl)-2-phenyl-2-butenal, (d) (Z)-4-acetoxy-3-(4-(methylsulfonyl)phenyl)-2-phenyl-2-butenoic acid and (e) (Z)-4-Acetoxy-3-(4-(methylsulfonyl)phenyl)-2-phenyl-2-butenoic acid methyl ester. 8. A compound according to claim 1 of formula Ia wherein 9. A compound according to claim 1 of formula Ib wherein 10. A pharmaceutical composition comprising a nontoxic therapeutically effective amount of a compound according to claim 1, 2, 3, 4, 5 or 6 or 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene and a pharmaceutically acceptable carrier. 11. A compound according to claim 1 selected from the group consisting of: (a) (Z)-2-(4-(Methylsulfonyl)phenyl)-3-(3,4-difluorophenyl)-2-butene-1,4-diol, (b) (Z)-2-(4-(Methylsulfonyl)phenyl)-3-(3,4-difluorophenyl)-2-butene-1,4-diol-1-acetate, (c) (Z)-4-Acetoxy-3-(4-(methylsulfonyl)phenyl)-2-(3,4-difluorophenyl)-2-butenal, (d) (Z)-4-acetoxy-3-(4-(methylsulfonyl)phenyl)-2-(3,4- difluorophenyl)-2-butenoic acid and (e) (Z)-4-Acetoxy-3-(4-(methylsulfonyl)phenyl)-2-(3,4-difluorophenyl)-2-butenoic acid sodium salt. 12. A pharmaceutically acceptable salt of a compound of formula (I) as defined in claim 1, 2, 3, 4, 5 or 6, or of the compound 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]- 1,4-dihydroxy-2-butene. 13. A compound of formula (I) as defined in claim 1, 2, 3, 4, 5 or 6 or 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory disease responsive to treatment with a non-steroidal anti-inflammatory drug. 14. The use of a compound of formula (I) as defined in claim 1, 2, 3, 4, 5 or 6 or of 2-(4-fluorophenyl)-3-[(4-methylsulfonyl)phenyl]-1,4-dihydroxy-2-butene or a pharmaceutical a therapeutically acceptable salt thereof for the manufacture of a medicament for the treatment of cyclooxygenase-mediated diseases which are advantageously treated by an agent which selectively inhibits COX-2 preferentially to COX-1.